We have found that elevation of circulatory Ia plus T cells, a feature of recent immunization in normal subjects, is present in the majority of rheumatoid arthritis patients. We postulate that the presence of the Ia antigens identifies a group of T cells generated by the immune challenges and committed to the causative agents. In the patients, this hypothesis will be tested by searching for and characterizing the progenitors of those cells in the synovial tissues, where the disease reaction is centered. In the immunized subjects, this will be tested by comparing the proliferative response of the Ia plus T cells to the immunizing and nonimmunizing antigens. A discontinuous density gradient has been designed for isolation of these cells. Ia negative T cells in these subjects and Ia plus T cells obtained by in vitro stimulation with antigens or mitogens will be studied for comparison. At the same time, the behavior of such cells will be studied in regard to their ability to modulate the induction of cells producing rheumatoid factor or secreting antibodies directed against the immunizing antigens. Finally, we have developed radioactive labelling and cell surface antigen isolation techniques to find out if the cells mediate their modifying activities by releasing their Ia antigens to react with receptors on another group of lymphocytes.